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?:abstract
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The rapid outbreak of SARS-Coronavirus 2 (SARS-CoV-2) caused a serious global public health threat The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design and discover new drugs to control Covid-19 disease Similarly, a transmembrane serine protease, TMPRSS2 of the host cell has been found to play a significant role in proteolytic cleavage of viral spike protein priming to the receptor ACE2 present in human cell However, three dimensional structure and inhibition mechanism of TMPRSS2 is yet to be explored experimentally Hence, in the present study we have generated a homology model of TMPRSS2 and studied its binding properties with experimentally studied inhibitors viz Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular docking technique Docking analysis revealed that the Camostat mesylate and its structural analogue Nafamostat interacts strongly with residues His296, Ser441 and Asp435 present in catalytic triad of TMPRSS2 However, BHH interacts with Gln438 and other residues present in the active site pocket of TMPRSS2 through hydrophobic contacts effectively Thus, these results revealed the inhibition mechanism of TMPRSS2 by known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride in detail at the molecular level However, Camostat mesylate shows strong binding as compared to other two inhibitors This structural information could also be useful to design and discover new inhibitors of TMPRSS2, which may be helpful to prevent the entry to SARS-Coronavirus 2 in human cell
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